英国谢菲尔德大学皇家哈勒姆郡医院Solomon Tesfaye团队比较了阿米替林补充普瑞巴林、普瑞巴林补充阿米替林、度洛西汀补充普瑞巴林治疗糖尿病周围神经病变性疼痛的疗效与安全性。2022年8月22日，《柳叶刀》杂志发表了这一成果。

糖尿病周围神经病理性疼痛（DPNP）是一种常见且令人痛苦的疼痛。大多数指南推荐阿米替林、度洛西汀、普瑞巴林或加巴喷丁作为DPNP的初始镇痛治疗，但关于哪一种是最好的或是否应联合使用的比较证据很少。该研究旨在评估不同一线药物组合治疗DPNP的疗效和耐受性。

研究组进行了一项多中心、随机、双盲、交叉试验，在英国13个中心招募平均每日疼痛数值评分（NRS）为4分或更高（评分为0-10）的DPNP患者。参与者被随机分配（1:1:1:1:1:1）：使用大小为6或12的排列块，按照预先确定的随机计划分层，分别接受三种治疗方案的六个有序序列中的一个：阿米替林补充普瑞巴林（A-P）、普瑞巴林补充阿米替林（P-A），度洛西汀补充普瑞巴林（D-P），每种疗法均持续16周。

单药治疗6周，如果疼痛缓解不理想（NRS>3），则补充联合用药，以反映当前临床实践。两种治疗均逐步增加至最大耐受剂量（阿米替林每天75毫克，度洛西汀每天120毫克，普瑞巴林每天600毫克）。主要结局是每种疗法最后一周7天平均每日疼痛的差异。

2017年11月14日至2019年7月29日，研究组共筛选了252名患者，随机分配了140名患者，130名患者开始了治疗方案（84名患者至少完成了两种方案），并对主要结局进行了分析。在所有三种方案中，第16周的7天平均NRS得分从基线时的平均6.6分降至第16周时的3.3分。

D-P组与A-P组的平均差异为-0.1分，P-A组与A-P组的平均差异为-0.1分，P-A组与D-P组的差异为0.0分，组间差异均不显著。接受联合治疗患者的平均NRS降低率大于接受单一治疗的患者（分别降低1.0分与0.2分）。单一疗法的不良事件可预测：研究组观察到P-A方案中的头晕、D-P方案中的恶心和A-P方案的口干显著增加。

这是有史以来规模最大、时间最长的头对头交叉神经病理性疼痛试验。研究组表明，所有三种治疗途径和单一疗法具有相似的镇痛效果。联合治疗具有良好的耐受性，并可改善单一治疗疼痛控制不佳患者的疼痛缓解。

附：英文原文

Title: Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial

Author: Solomon Tesfaye, Gordon Sloan, Jennifer Petrie, David White, Mike Bradburn, Stephen Julious, Satyan Rajbhandari, Sanjeev Sharma, Gerry Rayman, Ravikanth Gouni, Uazman Alam, Cindy Cooper, Amanda Loban, Katie Sutherland, Rachel Glover, Simon Waterhouse, Emily Turton, Michelle Horspool, Rajiv Gandhi, Deirdre Maguire, Edward B Jude, Syed H Ahmed, Prashanth Vas, Christian Hariman, Claire McDougall, Marion Devers, Vasileios Tsatlidis, Martin Johnson, Andrew S C Rice, Didier Bouhassira, David L Bennett, Dinesh Selvarajah

Issue&Volume: 2022-08-22

Abstract:

Background

Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP.

Methods

OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0–10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443.

Findings

Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was –0·1 (98·3% CI –0·5 to 0·3) for D-P versus A-P, –0·1 (–0·5 to 0·3) for P-A versus A-P, and 0·0 (–0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway.

Interpretation

To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy.

DOI: 10.1016/S0140-6736(22)01472-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01472-6/fulltext